Interleukin-6 (IL-6) is secreted by numerous blood cells. It is a 26-kDa protein composed of 183 amino acids in humans (Swissprot reference P05231). It can exert its biological effects on numerous cell types via specific membrane and soluble receptors.
IL-6 is one of the three major inflammatory cytokines, with IL-1 and TNF (Woo (1993) Clin. Exp. Rheumatol. 11 Suppl. 9:S29-32), inducing in particular the production of acute phase proteins by the liver (Nijsten et al. (1986) Lancet 2:921.16). IL-6 also plays an important role in bone and cartilage degradation (Jilka et al. (1992) Science 257:88-91, 1992), as well as in cartilage quality and proliferation of the synovial fibroblasts. In humans, it has been shown that overproduction of IL-6 is associated with rheumatoid arthritis (Robak et al. (1998) Mediators Inflamm. 7: 347-53) and it has been shown in several murine models of collagen-induced arthritis that IL-6 was necessary to the development of the disease, the mice in which the expression of IL-6 was abolished being completely protected (Alonzi et al. (1998) J. Exp. Med 187:461-8).
In the same way, the role of IL-6 as a primer has been demonstrated in other arthritic diseases, such as juvenile idiopathic arthritis, and also in chronic inflammatory diseases of the intestine (MICI) in humans (Mitsuyama et al. (1995) Gut 36:45-49), as well as in disseminated lupus erythematosus, in which an increase in IL-6 in the serum and an abnormal expression of the IL-6Rα receptor have been noted in a murine model. Moreover, the addition of exogenous IL-6 leads to increased production of auto-antibodies and more rapid progression of glomerulonephritis (Ryffel et al. (1994) Am. J. Pathol. 144:927-37).
Generally, pro-inflammatory cytokines such as IL-6, TNF, and IL-1 can be involved in the development of all of the chronic inflammatory diseases, such as                chronic inflammatory diseases of the intestine, such as Crohn's disease and haemorrhagic rectocolitis or ulcerous colitis,        arthritic diseases, in particular rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, arthrosis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, or ankylosing spondylitis,        chronic or IL-6-related inflammatory bone diseases, in particular a bone resorption disorder or osteoporosis,        chronic or IL-6-related inflammatory diseases associated with an infection, such as septic shock, endotoxin shock, septicaemia, HCV hepatitis, malaria, meningitis, AIDS or HIV infections,        chronic or IL-6-related inflammatory diseases of the cardiovascular system, such as atherosclerosis, ischaemia-reperfusion lesions, coronary diseases, and vasculitis, such as Behçet's disease or Wegener's granulomatosis,        auto-immune diseases, such as scleroderma, in particular systemic scleroderma, lupus erythematosus, in particular disseminated lupus erythematosus, multiple sclerosis, or psoriasis,        diseases linked to a graft, such as graft-versus-host reactions and graft rejections and traumas,        allergies, in particular allergic asthma and skin disorders due to delayed hypersensitivity reactions,        immune deficiencies, such as common variable immunodeficiency (CVID),        chronic or IL-6-related inflammatory diseases of the respiratory system, in particular respiratory distress syndrome or pulmonary fibrosis,        cancers having a chronic or IL-6-related inflammatory component, such as plasmacytoma, colorectal cancer, recurrent ovarian cancer, lymphoproliferative syndrome, multiple myeloma, in particular refractory multiple myeloma, or myeloproliferative syndrome,        diabetes, in particular juvenile diabetes,        amyloidosis, in particular Alzheimer's disease,        uveitis, in particular in its chronic recurrent form,        cachexia, or        endometriosis.        
Several strategies have been envisaged in an attempt to limit the harmful effects of IL-6.
Thus, a humanized monoclonal antibody, Tocilizumab, directed against the IL-6Rα receptor, is clinically effective in the treatment of rheumatoid arthritis in adults (Patel & Moreland (2010) Drug Design, Development and Therapy 4:263-278).
Moreover, monoclonal antibodies directly targeting the IL-6 cytokine are currently being developed in the context of the treatment of auto-immune diseases, such as the antibodies CNTO328 (US 2008/0081041) and CNTO136 (US 2010/0138945), but for the time being it does not seem that their clinical effectiveness has been established.
However, approaches making use of monoclonal antibodies, if they can be proved effective, are often expensive to implement, in particular because they require regular administrations of these antibodies.
In fact, a vaccination method for combating IL-6-related immune disorders using a human IL-6 mutein, Santl (De Benedetti et al. (2001) J. Immunol. 166:4334-4340; U.S. Pat. No. 6,706,261) has been described, but this work does not seem to have resulted in clinical development. Moreover, the vaccination of mice using mouse IL-6 mutants (mIL-6) makes it possible to obtain a protective immune response vis-à-vis collagen-induced arthritis or experimental allergic encephalitis (Galle et al. (2007) Int. Immunopharmacol. 7:1704-1713). However, in this case also, this work does not seem to have resulted in clinical development.